Pirfenidone, 5-methyl-1-phenyl-2(1H)-pyridinone, is a medicament for the treatment of idiopathic pulmonary fibrosis. It has antifibrotic and anti-inflammatory activities, preventing collagen production and fibroblast proliferation.
The literature describes numerous examples of Pirfenidone (1) synthesis starting with 2-amino-5-methylpyridine (2), the diazonium salt and subsequent carbonyl function of which are formed by one-pot synthesis to give the intermediate 5-methylpyridine-2(1H)-one (3). Subsequent arylation of the resulting intermediate leads to the formation of the compound of interest.

Patent DE2362958 discloses the second step in the synthesis of Pirfenidone (Example 1) from intermediate (3); the operating conditions involve the absence of solvent, the reflux temperature of iodobenzene, and the presence of copper powder and an inorganic base.

The purification involves decolourising with charcoal, followed by trituration in petroleum ether and subsequent crystallisation in water.
Patent WO2008147170 discloses the reaction of (3) and iodobenzene in the absence of solvent, mediated by copper powder in the presence of potassium carbonate and at the reflux temperature of iodobenzene.

The reaction is followed by an extraction process, treatment with charcoal, and crystallisation.
CN102558040 describes three examples (Examples 1, 2, 3) wherein pyridone intermediate (3) reacts with iodobenzene at its reflux temperature, in the presence of metallic copper and potassium carbonate, in the absence of solvent.

At the end of the reaction the iodobenzene is distilled, followed by a first crystallisation in ethyl acetate, a decolourising treatment with activated charcoal, and subsequent crystallisation from a water/ethanol mixture.
In patent CN1817862 (Example b), intermediate (3) is reacted with iodobenzene under reflux, in the absence of solvent and in the presence of potassium carbonate, but in this case the reaction is catalysed by CuCl.

At the end of the reaction an extraction process and acid/base crystallisation are performed.
WO2003014087 (Examples 1, 2, 3 and 4 and reference example) reports the synthesis of (1) by reacting intermediate (3) with bromobenzene at high temperatures in the presence of potassium carbonate and cuprous oxide.

The purification involves an extraction process, a charcoal treatment and acid/base crystallisation.
In patent CN101891676 the reaction between (3) and bromobenzene is always conducted in the absence of solvent, at the reflux temperature of bromobenzene, in the presence of potassium carbonate, but mediated by CuBr.

This is followed by distillation of the excess reagent, treatment with charcoal in an aqueous medium, and acid/base crystallisation.
CN1386737 refers to the arylation reaction with various mono-halo-benzene compounds, but does not cite any examples describing that synthetic step.
Patent WO2010141600 describes the synthesis of Pirfenidone (1) which, unlike the process described in the above-mentioned patents, is effected in the presence of a high-boiling solvent (DMF); the reaction is conducted with bromobenzene, claimed by the inventors as being characterised by a dibromobenzene content of less than 0.15% molar or weight/weight, cuprous oxide and potassium carbonate in an inert environment at 125° C.

When the reaction is complete, an extraction process, a charcoal treatment, a first crystallisation in a mixture of organic solvents and a second acid/base crystallisation are effected.
Some articles and patents present in the literature (such as DE2362958, CN1817862 and WO2003014087) mention chlorobenzene as a possible raw material in the synthesis of pirfenidone, but none of them describe the operating conditions with practical examples.
The use of chlorobenzene for the production of Pirfenidone is very interesting from the industrial standpoint as the price of chlorobenzene is far more advantageous than that of bromobenzene, and even more advantageous than that of iodobenzene.
On the basis of this advantage it has surprisingly been discovered that chlorobenzene can be used to synthesise Pirfenidone in industrial reactors which can operate not only at high pressures but also at atmosphere pressure.